Isotopically modified composition and therapeutic uses thereof

Abstract

This disclosure relates to isotopically modified amino acids and their pharmaceutical or nutritional uses in stabilizing pharmaceutical protein-based formulations, proteins with long life span, and preventing or treating disease such as Alzheimer's disease. Specifically, the disclosure provides protein drugs having increased stability comprising an L-aspartate (L-Asp) residue or an L-asparagine (L-Asn) residue, wherein the L-Asp residue or the L-Asn residue comprises a deuterium atom.

What is claimed is: 
     
         1 . A protein drug having increased stability comprising an L-Asp residue or an L-Asn residue, wherein the L-Asp residue or the L-Asn residue comprises a deuterium atom. 
     
     
         2 . The protein drug of  claim 1 , wherein the deuterium atom is located on the alpha carbon of the L-Asp residue or the L-Asn residue. 
     
     
         3 . The protein drug of  claim 1  or  2 , wherein the deuterium atom is located on the side chain methylene group. 
     
     
         4 . The protein drug of any one of  claims 1  to  3 , wherein the L-Asp residue or the L-Asn residue comprises at least two deuterium atoms. 
     
     
         5 . The protein drug of any one of  claims 1  to  4 , wherein the L-Asp residue or the L-Asn residue comprises at least three deuterium atoms. 
     
     
         6 . The protein drug of any one of  claims 1  to  5 , wherein the L-Asp residue or the L-Asn residue comprises a deuterium atom at every hydrogen position. 
     
     
         7 . The protein drug of any one of  claims 1  to  6 , wherein the racemization rate of the L-Asp residue or the L-Asn residue is at least 50% lower than the racemization rate of an L-Asp residue or an L-Asn residue having no deuterium atoms. 
     
     
         8 . The protein drug of any one of  claims 1  to  7 , wherein the protein drug has a half life after administration into a human subject that is at least 20% greater than a corresponding protein drug having no deuterium atoms at the L-Asp residue or the L-Asn residue. 
     
     
         9 . The protein drug of any one of  claims 1  to  8 , wherein the protein drug has a stability that is at least 20% greater than a corresponding protein drug having no deuterium atoms at the L-Asp residue or the L-Asn residue. 
     
     
         10 . A method of treating, ameliorating or preventing a disease in a human subject wherein the disease is caused by racemization of one or more Asp residues or one or more Asn residues in a protein, comprising administering to the human subject an effective amount of deuterated L-Asp or deuterated L-Asn. 
     
     
         11 . The method of  claim 10 , wherein at least 10% of the protein in the human subject is deuterated at the one or more Asp residues or the one or more Asn residues after the administration of deuterated L-Asp or deuterated L-Asn. 
     
     
         12 . The method of  claim 10  or  11 , wherein the racemization of the one or more Asp residues or the one or more Asn residues in the protein is decreased by at least 10% after the administration of deuterated L-Asp or deuterated L-Asn. 
     
     
         13 . The method of any one of  claims 10  to  12 , wherein the disease is Alzheimer's disease. 
     
     
         14 . The method of any one of  claims 10  to  13 , wherein the protein is amyloid-β. 
     
     
         15 . The method of  claim 14 , wherein the one or more Asp residues comprise Asp1, Asp7 and Asp23 of amyloid-β-42. 
     
     
         16 . The method of  claim 14 , wherein the one or more Asn residues comprise Asn27 of amyloid-β-42. 
     
     
         17 . The method of any one of  claims 10  to  16 , wherein the deuterated L-Asp or deuterated L-Asn is administered daily. 
     
     
         18 . A product comprising a deuterated L-Asp or a deuterated L-Asn residue, wherein the amount of deuterium in the produce is above the naturally occurring level. 
     
     
         19 . The product of  claim 18 , wherein the racemization of the L-Asp residue or the L-Asn residue in the product is decreased by at least 10% when the product is in liquid form. 
     
     
         20 . The product of  claim 18  or  19 , wherein the product is a protein. 
     
     
         21 . The product of any one of  claims 18  to  20 , wherein the product is Methyl L-α-aspartyl-L-phenylalaninate.